Project description
Tuberculosis: a persistent menace
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is the leading single infectious cause of death worldwide, claiming more than one million lives per year. Treatment is complicated by long duration, primary treatment failure, disease recurrence, and increasingly-prevalent drug resistance. All of these complications are linked to a phenomenon known as phenotypic tolerance, by which some bacteria within a drug-susceptible population transiently survive exposure to a drug without acquiring heritable resistance mutations. Tolerant cells—called persisters—are thus prime targets for new therapeutics that could improve outcomes in TB, but the mechanisms by which they survive would-be lethal antibiotic exposure remain a mystery. To understand this phenomenon, COMBATTB is uncovering the genetic factors and metabolic pathways that lead to phenotypic tolerance in Mycobacterium tuberculosis. The thorough understanding of these pathways will establish an essential foundation for building better, faster TB drug regimens that could help save countless lives.
Objective
Mycobacterium tuberculosis (Mtb) is one of about a dozen bacterial species for which some clinical isolates are now resistant to most or all antibiotics (abx) approved for treatment of the infections they cause. Mechanisms of antimicrobial resistance (AMR) in Mtb deserve study for their potential relevance to AMR in other pathogens; because tuberculosis (TB) is now the leading cause of death from infectious disease; and because drug-resistant TB may be the most prevalent of all drug-resistant bacterial infections. Heritable AMR in Mtb emerges with interruption of treatment, and the long duration of TB treatment provides many opportunities for interruption. Prolonged treatment is necessary because of nonheritable resistance, also called phenotypic tolerance or persistence, defined as the transient tolerance of bacteria in an antibiotic-sensitive population to an antibiotic during exposure to an otherwise lethal concentration of that antibiotic. In contrast to “resisters”, whose AMR is genetically encoded, “persisters” are genetically sensitive bacteria whose phenotypic tolerance allows them to survive for prolonged periods during what would otherwise be rapidly curative treatment. In addition, phenotypic tolerance is likely a source of treatment failure and a major contributor to TB reactivation after apparently effective treatment. The specific aims of this application are to identify genetic determinants that foster phenotypic tolerance in Mtb and decipher at a molecular level the mechanisms by which Mtb enters and maintains a persistent state.
Fields of science
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesclinical medicinepneumologytuberculosis
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Programme(s)
Funding Scheme
MSCA-IF-EF-RI - RI – Reintegration panelCoordinator
SW7 2AZ LONDON
United Kingdom